There is now convincing evidence that in addition to muscarinic-cholinergic receptors there are also nicotinic-cholinergic receptors in the mammalian central nervous system. We and others have observed that activation of nicotinic-cholinergic receptors leads to a release of both dopamine and serotonin in the striatum and hypothalamus. The objective of the present proposal is to focus on three important aspects of the nicotine-induced activation of dopaminergic and serotonergic neurotransmission. Firstly, we will determine the mechanism(s) by which activation of nicotinic receptors produces a release of these neurotransmitters. The binding of radioactive ligands (3H-nicotine; 3H-acetyl-choline) to rat striatal membranes will be examined before and after lesioning of various neural pathways (dopamine, serotonin, glutamate) to help identify the site of nicotinic receptors. The release of endogenous dopamine and serotonin from slices and synaptosomes (by HPLC-EC analysis) in the absence or presence of various drugs, ions, or perturbations will provide information on various aspects of the release process (e.g. importance of propagated action potentials, exocytosis, intermediate neuromediators, desensitization, additivity with other mechanisms of inducing transmitter release, etc.). Secondly, the role of opioid drugs and peptides on the nicotine induced release of dopamine and serotonin from striatal slices will be rigorously analyzed in an attempt to determine if they exert a neuromodulatory role. Finally, the effect of chronic treatment of rats with nicotinic agonists and antagonists on norepinephrine, dopamine and serotonin turnover in vivo and release in vitro as well as on the number and density of nicotinic receptors in vitro will be examined. These studies will provide important information on the mechanism and modulation of the release of dopamine, serotonin and possibly glutamate in the striatum following activation of nicotinic receptors. In addition, these experiments should provide valuable information concerning the adaptation of neurotransmitter systems following continual exposure to nicotinic agonists and antagonists. These results should relate much better to the possible effects of tobacco and nicotine abuse in man.